Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene

Abstract

All coauthors have reviewed the manuscript and have contributed in a substantive and intellectual manner to the work described. * Orna Steinberg-Shemer and Raz Somech had equal contribution. AbstractBackground: The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature. Methods: Two patients with neutropenia underwent hematological, immunological, and genetic work-up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole-exome sequencing, and in silico proteomic analysis. Results: Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life-threatening infection requiring leg amputation. Immunological and hematological work-up showed isolated neutropenia with normal lymphocyte subpopulations,immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in-frame deletion in the SRP54 gene, c.342-344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability. Conclusions:We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene. K E Y W O R D Scongenital neutropenia, signal recognition particle, SRP54, variable expressivity

NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia

“…SRP54 (Signal Recognition Particle 54) is a part of signal recognition particle (SRP), a ribonucleoprotein, that mediates the passage between the ribosomes and membrane associated protein-translocation machinery of the endoplasmic reticulum (ER). Recently, Goldberg et al reported a novel mutation (in frame deletion) that affects complex stability causing congenital neutropenia [ 45 ], as described also in previous studies [ 46 , 47 ].…”

Structural and Functional Impact of SRP54 Mutations Causing Severe Congenital Neutropenia

“…The mutation-dependent effect on GTP binding affinity can be correlated with the clinical phenotypes of patients. When considering all cases that have been reported so far in the literature, the majority of patients with mutations in the G1 element show milder phenotypes than those with mutations in the other G elements or in the ''GQ '' motif (Bellanne ´-Chantelot et al, 2018;Chippaux, 1987;Goldberg et al, 2020;Saettini et al, 2020). As patients are heterozygous, it is likely that mutations in the G1 element (T115A and T117del) that decrease the binding affinity for GTP interfere less efficiently with the function of the remaining WT copy of the protein than mutations affecting other regions and linked to other functional defects.…”

Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children

“…One additional patient, presenting with familial neutropenia and recurrent infections, was subsequently diagnosed by WES with a novel SRP54 variant causing SCN and SBDS. 25 , 36 This gene was not known to cause neutropenia at the time the NGS study was performed. We later incorporated this gene into the subsequent versions of our NGS panel and detected a variant in this gene in one more patient that had a re-do of the NGS panel.…”